TACI is mutant in common variable immunodeficiency and IgA deficiency.

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) is a receptor in the tumor necrosis factor receptor superfamily.
• TACI plays a crucial role in B cell function, specifically in mediating immunoglobulin (Ig) isotype switching.

Purpose of the Study:

• To investigate the role of TNFRSF13B gene mutations, encoding TACI, in patients with common variable immunodeficiency (CVID) and IgA deficiency (IgAD).
• To determine if identified mutations in TNFRSF13B correlate with impaired B cell isotype switching and antibody production.

Main Methods:

• Genetic analysis of the TNFRSF13B gene in unrelated individuals diagnosed with CVID and IgAD.
• Sequencing of TNFRSF13B alleles to identify missense mutations and insertions.
• Segregation analysis of TNFRSF13B mutations within families of affected individuals.
• Functional assessment of B cells from patients with TACI mutations, evaluating response to TACI ligand APRIL and antibody production (IgG, IgA).

Main Results:

• Missense mutations in one allele of TNFRSF13B were identified in 4 of 19 CVID patients and 1 of 16 IgAD patients.
• A single nucleotide insertion in the other TNFRSF13B allele was found in one CVID patient.
• No TNFRSF13B mutations were detected in 50 healthy control subjects.
• TNFRSF13B mutations cosegregated with CVID or IgAD phenotypes in affected families.
• B cells from individuals with TACI mutations expressed TACI but showed impaired IgG and IgA production upon stimulation with APRIL, indicating defective isotype switching.

Conclusions:

• Mutations in the TNFRSF13B gene, encoding TACI, are a potential cause of common variable immunodeficiency (CVID) and IgA deficiency (IgAD).
• Impaired B cell isotype switching, leading to reduced IgG and IgA production, is a likely consequence of these TACI mutations.